Computational biologists at St. Jude categorized and identified the mechanism underlying oncogenic fusions in pediatric cancer cells. The researchers showed in mice that targeting oncogenic fusions that drive cancer with genome editing tools such as CRISPR has the potential to cure certain tumors.
The findings were published in Nature Communications in a paper titled, “Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.”
“Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets,” wrote the researchers. “However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5,190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11.”
“We’ve made something similar to the periodic table in chemistry for types of oncogenic fusions,” said senior and co-corresponding author Xiaotu Ma, PhD, St. Jude department of computational biology. “By cataloging the underlying mechanisms, we’ve given other scientists the ability to study fusions in better detail.”
“It is now well established that fusion oncoproteins drive many pediatric cancers,” explained co-corresponding author Jeffery Klco, MD, PhD, St. Jude department of pathology. “The Ma lab has comprehensively characterized the full spectrum of oncogenic fusions in childhood cancer, providing the community which a rich resource that can be mined to develop more predictive clinical tests while also suggesting potential therapeutic strategies for some tumor types. This will be a hugely impactful study.”
The new St. Jude tool lays a foundation for using genome editing to cure cancer. The mutations that cause fusion genes are only present in cancer cells. That means a highly specific genetic engineering tool, such as the CRISPR-Cas9 system, could selectively cut out the fusion gene in cancer cells, which removes their ability to make the hybrid protein.
“The fusion gene specific sequence only exists in cancer cells,” said first author Yanling Liu, PhD, St. Jude department of computational biology. “It wouldn’t target any normal cells. We used CRISPR-Cas9 to perturb the fusion specific alleles in two cancer cell lines and killed them.”
“We were able to demonstrate the therapeutic potential of genome editing using CRISPR-Cas9 and in vitro cancer cell line models,” said co-corresponding author Shondra Pruett-Miller, PhD, director, St. Jude Center for Advanced Genome Engineering. “We believe this is just the tip of the iceberg in terms of how we might be able to harness the power of genome editing to target these oncofusions.”
Even with the challenges facing its use in therapy, the computational tool already predicts some clinical outcomes. The St. Jude authors were able to explain why a small group of pediatric patients with relapsed acute myeloid leukemia (AML) had poor outcomes. The result demonstrated that the tool can be used for clinical predictions, which will help physicians choose more personalized and effective treatments for patients in the future.
